Ozanimod Differentially Impacts Circulating Lymphocyte Subsets in Patients with Moderately to Severely Active Crohn's Disease.

BACKGROUND: Ozanimod showed efficacy and safety in the phase 2 STEPSTONE study conducted in patients with moderately to severely active Crohn's disease. AIMS: This analysis assessed the effects of ozanimod on circulating lymphocytes in Crohn's disease. METHODS: Patients received ozanimod 0.92 mg for 12 weeks. Lymphocyte subtypes were evaluated using multicolor flow analysis on blood samples collected before treatment and on Week 12. Absolute lymphocyte count changes were analyzed by Wilcoxon signed rank tests. Disease activity changes and efficacy outcomes were evaluated at Week 12, and associations with lymphocyte subtype levels were assessed using Spearman's correlation and logistic regression. RESULTS: Reductions in median total T, Th, and cytotoxic T cells occurred at Week 12 (45.4%-76.8%), with reductions in most subtypes of 47.5% to 91.3% (P < 0.001). CD8+ terminally differentiated effector memory cells were largely unaffected (median change, - 19%; P = 0.44). Reductions in median total B cells occurred at Week 12 (76.7%), with reductions in subtypes of 71.4% to 81.7% (P < 0.001). Natural killer and monocyte cell counts were unchanged. Greater baseline levels and changes in nonswitched memory B cells were significantly associated with clinical, endoscopic, and histologic efficacy (P < 0.05, all comparisons). CONCLUSIONS: Ozanimod reduced circulating levels of all B-cell and most T-cell subsets but not monocytes or natural killer cells. Key subsets relevant to immune surveillance were not reduced, supporting the low risk of infection and malignancy with ozanimod in chronic inflammatory diseases. Levels of nonswitched memory B cells were associated with efficacy, providing a potential marker for ozanimod response. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02531113, EudraCT: 2015-002025-19.

Simulated cost-effectiveness of a novel precision-guided dosing strategy in adult patients with Crohn's disease initiating infliximab maintenance therapy.

BACKGROUND: Patients with Crohn's disease (CD) who lose response to biologics experience reduced quality of life (QoL) and costly hospitalizations. Precision-guided dosing (PGD) provides a comprehensive pharmacokinetic (PK) profile that allows for biologic dosing to be personalized. We analyzed the cost-effectiveness of infliximab (IFX) PGD relative to two other dose intensification strategies (DIS). METHODS: We developed a hybrid (Markov and decision tree) model of patients with CD who had a clinical response to IFX induction. The analysis had a US payer perspective, a base case time horizon of 5 years, and a 4-week cycle length. There were three IFX dosing comparators: PGD; dose intensification based on symptoms, inflammatory markers, and trough IFX concentration (DIS1); and dose intensification based on symptoms alone (DIS2). Patients that failed IFX initiated ustekinumab, followed by vedolizumab, and conventional therapy. Transition probabilities for IFX were estimated from real-world clinical PK data and interventional clinical trial patient-level data. All other transition probabilities were derived from published randomized clinical trials and cost-effectiveness analyses. Utility values were sourced from previous health technology assessments. Direct costs included biologic acquisition and infusion, surgeries and procedures, conventional therapy, and lab testing. The primary outcomes were incremental cost-effectiveness ratios (ICERs). The robustness of results was assessed via one-way sensitivity, scenario, and probabilistic sensitivity analyses (PSA). RESULTS: PGD was the cost-effective IFX dosing strategy with an ICER of 122,932 $ per quality-adjusted life year (QALY) relative to DIS1 and dominating DIS2. PGD had the lowest percentage (1.1%) of patients requiring a new biologic through 5 years (8.9% and 74.4% for DIS1 and DIS2, respectively). One-way sensitivity analysis demonstrated that the cost-effectiveness of PGD was most sensitive to the time between IFX doses. PSA demonstrated that joint parameter uncertainty had moderate impact on some results. CONCLUSIONS: PGD provides clinical and QoL benefits by maintaining remission and avoiding IFX failure; it is the most cost-effective under conservative assumptions.

Exposure-efficacy relationship of vedolizumab subcutaneous and intravenous formulations in Crohn's disease and ulcerative colitis.

BACKGROUND AND AIMS: This posthoc analysis of the GEMINI and VISIBLE studies in ulcerative colitis (UC) and Crohn's Disease (CD) assessed exposure-efficacy of vedolizumab intravenous (IV) and subcutaneous (SC). METHODS: A previously described population pharmacokinetic model was used to predict average serum and trough concentrations at steady state (Cav,ss, Ctrough,ss) and simulate the transition from vedolizumab IV to SC. Efficacy was defined as clinical remission at week 52: complete Mayo score ≤ 2 points and no individual subscore > 1 point (UC), and CD activity index score ≤ 150 points (CD). RESULTS: Data were from 1968 patients (GEMINI 1 [n = 334], VISIBLE 1 [n = 216], GEMINI 2 [n = 1009], VISIBLE 2 [n = 409]) who received maintenance treatment with vedolizumab IV-Q8W, IV-Q4W, SC-Q2W, or placebo. Model-predicted Cav,ss for IV-Q8W and SC-Q2W was similar in UC and CD. Cav,ss was higher for IV-Q4W than IV-Q8W and SC-Q2W. Ctrough,ss values from IV and SC aligned well with pooled observed Ctrough by treatment group in UC and CD. Cav,ss was equivalent for SC and IV. For UC and CD, efficacy rates were greater in patients in the highest quartiles of vedolizumab exposure for both formulations. CONCLUSION: Exposure-efficacy relationships for IV and SC vedolizumab administration were comparable, confirming that both are equally effective during maintenance treatment.

Histologic assessments in ulcerative colitis: the evidence behind a new endpoint in clinical trials.

INTRODUCTION: Treatment goals for ulcerative colitis (UC) are evolving from the achievement of clinical remission to more rigorous goals defined by endoscopic and histologic healing. Achievement of deeper remission targets aims to reduce the risk of colectomy, hospitalizations, and colorectal cancer. AREAS COVERED: This review covers histologic assessments, histologic remission as a clinical trial endpoint, and the association between histologic disease activity and clinical outcomes. Future directions are also discussed, including the use of advanced imaging and artificial intelligence technologies, as well as potential future treatment targets beyond histologic remission. EXPERT OPINION: Histologic assessments are used for their sensitivity in measuring mucosal inflammatory changes in UC. Due to correlation with disease activity, histologic assessments may support clinical decision-making regarding treatment decisions as such assessments can be associated with rates of clinical relapse, hospitalization, colectomy, and neoplasia. While histologic remission is limited by varying definitions and multiple histologic indices, work is ongoing to create a consensus on the use of histologic assessments in clinical trials. As research advances, aspirational targets beyond histologic remission, such as molecular healing and disease clearance, are being explored.

Ulcerative colitis (UC) is the most common inflammatory bowel disease and often results in bloody diarrhea, frequent bowel movements, and bowel urgency. Patients with UC are at greater risk for hospitalization, surgery, and colorectal cancer. To reduce these risks, the goals of UC treatment are changing from mainly addressing symptoms to reducing inflammation at a deeper histologic, or microscopic, level. The inflammation in UC causes distinct microscopic changes in the colon, which can be assessed after collecting biopsies or tissue samples. This review provides an overview of histologic remission (when no signs of inflammation are seen in tissue samples viewed under a microscope) as a treatment goal in UC.Histologic remission has been shown to be associated with lower rates of relapse, hospitalization, surgical removal of the colon, and colorectal cancer. However, using histologic remission as a treatment target can be difficult due to varying definitions and the many different scoring assessments available to healthcare providers. Updated guidance from regulatory agencies and academic organizations has helped align definitions of histologic remission and how to assess histologic healing in clinical trials.The introduction of targeted advanced therapies has allowed for deeper healing with the potential for histologic resolution. This enables clinicians and researchers to aim for treatment targets that are harder to achieve but have a greater impact for patients in the course of their disease. New technologies such as artificial intelligence, high-resolution endoscopy, and digital pathology have also led to targets beyond histologic healing, aiming to restore the function of the colon's mucosal barrier and disease clearance.

Clinical statistical analysis plan for the ACCURE trial: the effect of appendectomy on the clinical course of ulcerative colitis, a randomised international multicentre trial.

BACKGROUND: The primary treatment of ulcerative colitis (UC) is medical therapy using a standard step-up approach. An appendectomy might modulate the clinical course of UC, decreasing the incidence of relapses and reducing need for medication. The objective of the ACCURE trial is to assess the efficacy of laparoscopic appendectomy in addition to standard medical treatment in maintaining remission in UC patients. This article presents the statistical analysis plan to evaluate the outcomes of the ACCURE trial. DESIGN AND METHODS: The ACCURE trial was designed as a multicentre, randomised controlled trial. UC patients with a new diagnosis or a disease relapse within the past 12 months, treated with 5-ASA, corticosteroids, or immunomodulators until complete clinical and endoscopic remission (defined as total Mayo score < 3 with endoscopic subscore of 0 or 1), were counselled for inclusion. Also, patients previously treated with biologicals who had a washout period of at least 3 months were considered for inclusion. Patients were randomised (1:1) to laparoscopic appendectomy plus maintenance treatment or a control group (maintenance therapy only). The primary outcome is the 1-year UC relapse rate (defined as a total Mayo-score ≥ 5 with endoscopic subscore of 2 or 3, or clinically as an exacerbation of symptoms and rectal bleeding or FCP > 150 or intensified medical therapy other than 5-ASA therapy). Secondary outcomes include number of relapses per patient, time to first relapse, disease activity, number of colectomies, medication usage, and health-related quality of life. DISCUSSION: The ACCURE trial will provide comprehensive evidence whether adding an appendectomy to maintenance treatment is superior to maintenance treatment only in maintaining remission in UC patients. TRIAL REGISTRATION: Dutch Trial Register (NTR) NTR2883 . Registered May 3, 2011. ISRCTN, ISRCTN60945764 . Registered August 12, 2019.

Crohn's Patient Serum Proteomics Reveals Response Signature for Infliximab but not Vedolizumab.

BACKGROUND: Crohn's disease is a chronic inflammatory bowel disease that affects the gastrointestinal tract. Common biologic families used to treat Crohn's are tumor necrosis factor (TNF)-α blockers (infliximab and adalimumab) and immune cell adhesion blockers (vedolizumab). Given their differing mechanisms of action, the ability to monitor response and predict treatment efficacy via easy-to-obtain blood draws remains an unmet need. METHODS: To investigate these gaps in knowledge, we leveraged 2 prospective cohorts (LOVE-CD, TAILORIX) and profiled their serum using high-dimensional isobaric-labeled proteomics before treatment and 6 weeks after treatment initiation with either vedolizumab or infliximab. RESULTS: The proportion of patients endoscopically responding to treatment was comparable among infliximab and vedolizumab cohorts; however, the impact of vedolizumab on patient sera was negligible. In contrast, infliximab treatment induced a robust response including increased blood-gas regulatory response proteins, and concomitant decreases in inflammation-related proteins. Further analysis comparing infliximab responders and nonresponders revealed a lingering innate immune enrichments in nonresponders and a unique protease regulation signature related to clotting cascades in responders. Lastly, using samples prior to infliximab treatment, we highlight serum protein biomarkers that potentially predict a positive response to infliximab treatment. CONCLUSIONS: These results will positively impact the determination of appropriate patient treatment and inform the selection of clinical trial outcome metrics.

A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial.

BACKGROUND: Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies. METHODS: PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 µg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 µg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228). FINDINGS: Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight). INTERPRETATION: Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease. FUNDING: Wellcome and PredictImmune Ltd.

mRNA-1273 vaccinated inflammatory bowel disease patients receiving TNF inhibitors develop broad and robust SARS-CoV-2-specific CD8+ T cell responses.

SARS-CoV-2-specific CD8+ T cells recognize conserved viral peptides and in the absence of cross-reactive antibodies form an important line of protection against emerging viral variants as they ameliorate disease severity. SARS-CoV-2 mRNA vaccines induce robust spike-specific antibody and T cell responses in healthy individuals, but their effectiveness in patients with chronic immune-mediated inflammatory disorders (IMIDs) is less well defined. These patients are often treated with systemic immunosuppressants, which may negatively affect vaccine-induced immunity. Indeed, TNF inhibitor (TNFi)-treated inflammatory bowel disease (IBD) patients display reduced ability to maintain SARS-CoV-2 antibody responses post-vaccination, yet the effects on CD8+ T cells remain unclear. Here, we analyzed the impact of IBD and TNFi treatment on mRNA-1273 vaccine-induced CD8+ T cell responses compared to healthy controls in SARS-CoV-2 experienced and inexperienced patients. CD8+ T cells were analyzed for their ability to recognize 32 SARS-CoV-2-specific epitopes, restricted by 10 common HLA class I allotypes using heterotetramer combinatorial coding. This strategy allowed in-depth ex vivo profiling of the vaccine-induced CD8+ T cell responses using phenotypic and activation markers. mRNA vaccination of TNFi-treated and untreated IBD patients induced robust spike-specific CD8+ T cell responses with a predominant central memory and activated phenotype, comparable to those in healthy controls. Prominent non-spike-specific CD8+ T cell responses were observed in SARS-CoV-2 experienced donors prior to vaccination. Non-spike-specific CD8+ T cells persisted and spike-specific CD8+ T cells notably expanded after vaccination in these patient cohorts. Our data demonstrate that regardless of TNFi treatment or prior SARS-CoV-2 infection, IBD patients benefit from vaccination by inducing a robust spike-specific CD8+ T cell response.

Efficacy of vedolizumab during intravenous induction therapy in ulcerative colitis and Crohn's disease: post hoc analysis of patient-reported outcomes from the VISIBLE 1 and 2 studies.

BACKGROUND: Vedolizumab is an anti-α4ß7 integrin antibody used to treat moderate to severe ulcerative colitis (UC) and Crohn's disease (CD). This post hoc analysis of patient-reported outcomes (PROs) from the VISIBLE 1 (NCT02611830) and 2 (NCT02611817) phase 3 studies evaluated onset of treatment effect on patient-reported symptoms during 6-week vedolizumab induction. METHODS: Patient-reported stool frequency (SF) and rectal bleeding (RB) (UC Mayo score), and SF and abdominal pain (AP) in CD were collected via electronic diary from VISIBLE patients receiving one or more open-label intravenous (IV) vedolizumab induction doses (weeks 0 and 2). PRO data were analyzed using descriptive statistics. RESULTS: Data from 994 patients (UC 383, CD 611) showed mean ratings for all PROs declined consistently week-on-week from baseline through week 6, with early onset of improvement. By week 2, 22% of patients with UC reported RB improvement (≥1-point reduction in RB subscore, 7-day mean), rising to 45% by week 6. By week 6, 18% of patients with UC achieved SF improvement (SF subscore 0; 21% antitumor necrosis factor alpha [anti-TNFα] naive, 13% anti-TNFα experienced). SF improvement in patients with CD (reduction of ≥3 stools, 7-day mean) was achieved by 32% at week 6 (34% anti-TNFα naive, 30% anti-TNFα experienced). Fewer patients with CD reported severe/moderate AP at week 6 (5.1%/28.5%) than baseline (14.6%/61.5%). SF decline appeared greater and faster for anti-TNFα-naive vs. anti-TNFα-experienced patients (UC and CD). CONCLUSION: Results indicate early onset of patient-reported UC and CD symptom improvement during vedolizumab IV induction in VISIBLE 1 and 2.

Switching from intravenous to subcutaneous infliximab maintenance therapy in inflammatory bowel disease: Post hoc longitudinal analysis of a randomized trial.

BACKGROUND: Pharmacokinetic non-inferiority of subcutaneous (SC) to intravenous (IV) CT-P13 maintenance therapy was demonstrated in a randomized trial (NCT02883452). This post hoc analysis evaluated longitudinal clinical outcomes with the two infliximab treatment strategies. METHODS: Patients with Crohn's disease or ulcerative colitis received CT­P13 IV loading doses (5 mg/kg; Week [W] 0 and W2) before randomization (1:1) to receive CT-P13 SC (body weight-based dosing every 2 weeks [Q2W]; W6-54; 'SC maintenance group') or CT­P13 IV (5 mg/kg Q8W; W6-22) then CT-P13 SC (Q2W; W30-54; 'IV-to-SC switch group'). Paired W30/W54 patient-level data were analyzed. RESULTS: Fifty-three (IV-to-SC switch) and fifty-nine (SC maintenance) patients were analyzed. Median trough serum CT-P13 concentrations were significantly higher at W54 versus W30 in the IV-to-SC switch group (20.4 versus 2.3 µg/mL; p < 0.00001), while remaining consistent in the SC maintenance group. Statistically significant improvements in pharmacokinetics, efficacy, fecal calprotectin levels, and quality of life were seen following switch to SC administration at W30 in the IV-to-SC switch group; safety findings were similar pre- and post-switch. CONCLUSION: Formulation switching from IV to SC infliximab maintenance therapy was well tolerated and may provide additional clinical improvements. Findings require confirmation in larger prospective studies.

Determining the optimal treatment target in patients with ulcerative colitis: rationale, design, protocol and interim analysis for the randomised controlled VERDICT trial.

INTRODUCTION: Symptoms, endoscopy and histology have been proposed as therapeutic targets in ulcerative colitis (UC). Observational studies suggest that the achievement of histologic remission may be associated with a lower risk of complications, compared with the achievement of endoscopic remission alone. The actiVE ulcerative colitis, a RanDomIsed Controlled Trial (VERDICT) aims to determine the optimal treatment target in patients with UC. METHODS AND ANALYSIS: In this multicentre, prospective randomised study, 660 patients with moderate to severe UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2) are randomly assigned to three treatment targets: corticosteroid-free symptomatic remission (Mayo RBS=0) (group 1); corticosteroid-free endoscopic remission (MES ≤1) and symptomatic remission (group 2); or corticosteroid-free histologic remission (Geboes score <2B.0), endoscopic remission and symptomatic remission (group 3). Treatment is escalated using vedolizumab according to a treatment algorithm that is dependent on the patient's baseline UC therapy until the target is achieved at weeks 16, 32 or 48. The primary outcome, the time from target achievement to a UC-related complication, will be compared between groups 1 and 3 using a Cox proportional hazards model. ETHICS AND DISSEMINATION: The study was approved by ethics committees at the country level or at individual sites as per individual country requirements. A full list of ethics committees is available on request. Study results will be disseminated in peer-reviewed journals and at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT: 2019-002485-12; NCT04259138.

DIAGNOSTIC ACCURACY OF INTESTINAL ULTRASOUND IN THE DETECTION OF INTRA-ABDOMINAL COMPLICATIONS IN CROHN'S DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS.

BACKGROUND: Crohn's disease (CD) is frequently associated with the development of strictures and penetrating complications. Intestinal ultrasound (IUS) is a non-invasive imaging modality ideal for point-of-care assessment. In this systematic review and meta-analysis we provide a current overview on the diagnostic accuracy of IUS and its advanced modalities in the detection of intra-abdominal complications in CD compared to endoscopy, cross-sectional imaging, surgery and pathology. METHOD: We conducted a literature search for studies describing diagnostic accuracy of IUS in adult patients with CD related intra-abdominal complications. Quality of the included studies was assessed with the QUADAS-2 tool. Meta-analysis was performed for both conventional IUS (B-mode) and oral contrast IUS (SICUS). RESULTS: Of the 1498 studies we identified, 68 were included in this review and 23 studies (3863 patients) were used for the meta-analysis. Pooled sensitivities and specificities for strictures, inflammatory masses and fistulas by B-mode IUS were 0.81 and 0.90, 0.87 (sensitivities) and 0.95, and 0.67 and 0.97 (specificities), respectively. Pooled overall log diagnostic odds ratios were 3.56, 3.97 and 3.84 respectively. Pooled sensitivity and specificity of SICUS were 0.94 and 0.95, 0.91 and 0.97 (sensitivities), and 0.90 and 0.94 (specificities), respectively. Pooled overall log diagnostic odds ratio of SICUS were 4.51, 5.46 and 4.80, respectively. CONCLUSION: IUS is accurate for the diagnosis of intra-abdominal complications in CD. As a non-invasive, point-of-care modality, IUS is recommended as the first-line imaging tool if there is a suspicion of CD-related intra-abdominal complications.

Defining Magnetic Resonance Imaging Treatment Response and Remission in Crohn's Disease: A Systematic Review.

BACKGROUND: Magnetic resonance imaging is increasingly used to assess treatment response in Crohn's disease clinical trials. We aimed to describe the definition of MRI response and remission as assessed by magnetic resonance enterography [MRE] to evaluate treatment efficacy in these patients. METHODS: Electronic databases were searched up to May 1, 2023. All published studies enrolling patients with inflammatory bowel disease and assessment of treatment efficacy with MRE were eligible for inclusion. RESULTS: Eighteen studies were included. All studies were performed in patients with Crohn's disease. The study period ranged from 2008 to 2023. The majority of studies used endoscopy as the reference standard [61.1%]. MRE response was defined in 11 studies [61.1%]. Five scores and nine different definitions were proposed for MRE response. MRE remission was defined in 12 studies [66.7%]. Three scores and nine different definitions for MRE remission were described. The MaRIA score was the most frequent index used to evaluate MRE response [63.6%] and remission [41.7%]. MRE response was defined as MaRIA score <11 in 63.6% of studies using this index. In 60% of studies using the MaRIA score, MRE remission was defined as MaRIA score <7. In addition, 11 different time points of assessment were reported, ranging from 6 weeks to years. CONCLUSION: In this systematic review, significant heterogeneity in the definition of MRE response and remission evaluated in patients with Crohn's disease was observed. Harmonization of eligibility and outcome criteria for MRE in Crohn's Disease clinical trials is needed.

Discontinuation of Anti-Tumour Necrosis Factor Therapy in Patients with Perianal Fistulizing Crohn's Disease: Individual Participant Data Meta-Analysis of 309 Patients from 12 Studies.

BACKGROUND: The risk of relapse after anti-tumour necrosis factor [TNF] therapy discontinuation in Crohn's disease patients with perianal fistulas [pCD] is unclear. We aimed to assess this risk. METHODS: A systematic literature search was conducted to identify cohort studies on the incidence of relapse following anti-TNF discontinuation in pCD patients. Individual participant data were requested from the original study cohorts. Inclusion criteria were age ≥16 years, pCD as a (co)indication for start of anti-TNF therapy, more than three doses, and remission of luminal and pCD at anti-TNF discontinuation. The primary outcome was the cumulative incidence of CD relapse using Kaplan-Meier estimates. Secondary outcomes included response to re-treatment and risk factors associated with relapse as assessed by Cox regression analysis. RESULTS: In total, 309 patients from 12 studies in ten countries were included. The median duration of anti-TNF treatment was 14 months [interquartile range 5.8-32.5]. Most patients were treated for pCD without active luminal disease [89%], received first-line anti-TNF therapy [87%], and continued immunomodulatory therapy following anti-TNF discontinuation [78%]. The overall cumulative incidence of relapse was 36% (95% confidence interval [CI] 25-48%) and 42% [95% CI 32-53%] at 1 and 2 years after anti-TNF discontinuation, respectively. Risk factors for relapse included smoking (hazard ratio [HR] 1.5 [1.0, 2.1]) and history of proctitis (HR 1.7 [1.1, 2.5]). The overall re-treatment response rate was 82%. CONCLUSIONS: This individual participant data meta-analysis, on predominantly patients with pCD without active luminal disease and first-line anti-TNF therapy, shows that over half of patients remain in remission 2 years after anti-TNF discontinuation. Therefore, anti-TNF discontinuation may be considered in this subgroup.

Clinical trial: Clinical and endoscopic outcomes with ustekinumab in patients with Crohn's disease: Results from the long-term extension period of STARDUST.

BACKGROUND: STARDUST, a phase 3b randomised trial, compared ustekinumab therapeutic strategies in patients with Crohn's disease (CD) using early endoscopic assessment and treat-to-target (T2T) versus standard of care (SoC). AIM: To assess the efficacy of ustekinumab extended treatment in a long-term extension (LTE) of up to 104 weeks with dosing adapted according to clinical, biomarker and endoscopy outcomes. METHODS: Adults with moderately-to-severely active CD received intravenous ustekinumab approximating 6 mg/kg at Week 0 and subcutaneous ustekinumab 90 mg at Week 8. At Week 16, 440 ≥70-point responders were randomised to T2T or SoC and 323 entered the LTE. At Week 48, a unified, protocol-defined ustekinumab dose frequency escalation/de-escalation was applied based on achieving endoscopic remission and corticosteroid-free clinical remission. Achieving corticosteroid-free clinical remission and biomarker remission at consecutive visits determined ustekinumab dosing frequency. Dichotomous variables were analysed using non-responder imputation. RESULTS: Among patients who entered the LTE, 7.7%, 48.6% and 43.7% received doses every 4, 8 and 12 weeks, respectively. Ustekinumab dose frequency was escalated in 23.5% and de-escalated in 19.7%. Endoscopic response and remission rates were 28.9% and 10.73% (all randomised) and 39.3% and 14.6% (patients entering the LTE), respectively, at Week 104. Clinical remissiona rates at week 104 were 50.2% (all randomised) and 68.4% (patients entering the LTE). There were no new safety signals. CONCLUSION: STARDUST LTE is the first interventional ustekinumab efficacy study to show a favourable benefit-risk profile with preservation of clinical and endoscopic outcomes through Week 104 using flexible, algorithm-driven dose adjustment including de-escalation.

Anti-drug antibodies against anti-TNF in patients with inflammatory bowel disease: an evaluation of possible strategies.

OBJECTIVE: Immunogenicity against anti-TNF antibodies usually leads to loss of response. We aimed to evaluate the efficacy of clinical strategies to improve clinical remission and pharmacokinetics upon detection of anti-drug antibodies (ADA). METHODS: Inflammatory bowel disease (IBD) patients with ADA against infliximab or adalimumab were identified through a single centre database search covering 2004-2022. Criteria for successful intervention upon ADA detection (baseline) were clinical remission after 1 year without further change in strategy. RESULTS: Two-hundred-and-fifty-five IBD patients (206 Crohn's disease) were identified. At baseline, median ADA level was 77 AU/ml; 50.2% of patients were in clinical remission. Implemented strategies were: (1) 81/255 (32%) conservative management, (2) 102/255 (40%) anti-TNF optimisation, (3) 72/255 (28%) switch within or out of class. Switching was the most successful strategy for clinical remission (from 19% at baseline to 69% at 1 year, p < 0.001). Patients that continued the same dose anti-TNF or discontinued biological therapy were often in clinical remission, but deteriorated significantly (-22.7%, p = 0.004). Anti-TNF dose intensification with immunomodulator optimisation was the fastest (median 3.0 months, p = 0.009) and most effective (65% ADA suppression, p < 0.001) strategy to suppress ADA compared to solely anti-TNF or immunomodulator optimisation. CONCLUSIONS: Switching therapy, within or out of class, is the most successful strategy to regain and maintain clinical remission upon immunogenicity. When switching to another anti-TNF, concomitant immunomodulatory therapy should be started or continued to prevent repeated immunogenic loss of response. Anti-TNF dose escalation with concomitant immunomodulator optimisation is the fastest and most effective strategy to suppress ADA.

Immunogenicity against anti-TNF antibodies is associated with loss of response in patients with inflammatory bowel diseases and remains a clinical challenge. We investigated potential therapeutic strategies in a retrospective patient cohort focusing on clinical efficacy and pharmacokinetics.

Efficacy and safety of 48 weeks of guselkumab for patients with Crohn's disease: maintenance results from the phase 2, randomised, double-blind GALAXI-1 trial.

BACKGROUND: Many patients with moderately to severely active Crohn's disease do not respond to available therapies or lose response over time. The GALAXI-1 study previously found that three intravenous guselkumab dosages showed superior clinical and endoscopic outcomes over placebo at week 12 in patients with moderately to severely active Crohn's disease. We report the safety and efficacy of subcutaneous guselkumab maintenance regimens to week 48 in the GALAXI-1 study. METHODS: We did a phase 2, randomised, multicentre, double-blind trial. Adult patients with moderately to severely active Crohn's disease were randomly allocated with a computer-generated randomisation schedule to receive one of five treatment groups, with regimens consisting of an intravenous induction phase transitioning to a subcutaneous maintenance phase starting at week 12 in a treat-through design: (1) guselkumab 200→100 mg group (200 mg intravenous at weeks 0, 4, and 8, then 100 mg subcutaneous every 8 weeks; (2) guselkumab 600→200 mg group (600 mg intravenous at weeks 0, 4, and 8, then 200 mg subcutaneous every 4 weeks); (3) guselkumab 1200→200 mg group (1200 mg intravenous at weeks 0, 4, and 8, then 200 mg subcutaneous every 4 weeks); (4) ustekinumab group (approximately 6 mg/kg intravenous at week 0, then 90 mg subcutaneous every 8 weeks); or (5) placebo group (placebo induction followed by either placebo maintenance [for those with CDAI clinical response at week 12] or crossover to ustekinumab [for those without CDAI clinical response at week 12]). Endpoints assessed at week 48 included CDAI remission (CDAI score <150), endoscopic response (≥50% improvement from baseline in SES-CD or SES-CD score ≤2), and endoscopic remission (SES-CD score ≤2) in the primary efficacy analysis population of all randomised patients who received at least one dose of study drug, excluding those discontinued during a temporary study pause. Safety analyses included all randomised patients who received at least one study drug dose. This trial is registered at Clinical Trials.gov (NCT03466411) and is active but not recruiting. FINDINGS: Among 700 patients screened, 309 (112 biologic-naive; 197 biologic-experienced) were included in the primary efficacy analysis population: 61 in the guselkumab 200→100 mg group, 63 in the guselkumab 600→200 mg group, 61 in the guselkumab 1200→200 mg group, 63 in the ustekinumab group, and 61 in the placebo group. 126 (41%) women and 183 (59%) men were included, with median age 36·0 years (IQR 28·0-49·0). At week 48, the numbers of patients with CDAI clinical remission were 39 (64%) in the guselkumab 200→100 mg group, 46 (73%) in the guselkumab 600→200 mg group, 35 (57%) in the guselkumab 1200→200 mg group, and 37 (59%) in the ustekinumab group. The corresponding numbers of patients with endoscopic response were 27 (44%), 29 (46%), 27 (44%), and 19 (30%), respectively, and endoscopic remission was seen in 11 (18%), 11 (17%), 20 (33%), and four (6%) patients, respectively. In the placebo group, 15 patients were in CDAI clinical response at week 12 and continued placebo; of these, nine (60%) were in clinical remission at week 48. 44 patients in the placebo group were not in CDAI clinical response at week 12 and crossed over to ustekinumab; of these, 26 (59%) were in clinical remission at week 48. Up to week 48, adverse events frequencies in the safety population (n=360) were 46 (66%) of 70 patients (464·9 events per 100 patient-years of follow-up) in the placebo group, 163 (74%) of 220 patients (353·1 per 100 patient-years) in the three guselkumab groups combined, and 60 (85%) of 71 patients (350·7 per 100 patient-years) in the ustekinumab group. Among patients treated with guselkumab or ustekinumab, the most frequently reported infections up to week 48 were nasopharyngitis (25 [11%] of 220 guselkumab recipients, 12 [11%] of 114 ustekinumab recipients) and upper respiratory infections (13 [6%] guselkumab recipients, eight [7%] ustekinumab recipients). After week 12, one patient who responded to placebo induction and two guselkumab-treated patients had serious infections. No active tuberculosis, opportunistic infections, or deaths occurred. INTERPRETATION: Patients receiving guselkumab intravenous induction and subcutaneous maintenance treatment achieved high rates of clinical and endoscopic efficacy up to week 48. No new safety concerns were identified. FUNDING: Janssen Research & Development.

The clinical relevance of an inflamed appendix in Crohn's disease.

BACKGROUND AND AIMS: An appendectomy for appendiceal inflammation has been suggested to ameliorate the clinical course of patients with ulcerative colitis (UC). In contrast, for Crohn's disease (CD) an inverse association has been suggested with a higher incidence of CD and worse prognosis after appendectomy. The aim of this study was to analyse the clinical relevance of an inflamed appendix in CD patients undergoing ileocoecal resection (ICR). METHODS: All consecutive patients undergoing primary ICR between 2007 and 2018 were considered for inclusion. Microscopic data of available appendiceal resection specimens (n=99) were revised by a dedicated IBD-pathologist and scored as inflamed or not inflamed. Eighteen patients had a previous appendectomy. Pathological findings were correlated with disease characteristics and recurrence rates (clinical, endoscopic and intervention-related). RESULTS: In total, 117 patients were included: 77 (65.8%) females with a median age of 30 years [IQR 24 - 43] with a median follow up of 102 months [IQR 76-114]. Of patients without previous appendectomy (n=99), 39% had an inflamed appendix. No significant differences in disease characteristics (e.g. disease location, behaviour, time to surgery) or prognosis could be demonstrated between the two groups. In contrast, previous appendectomy (n=18) was associated with penetrating disease and numerically shorter disease duration at the time of resection. Furthermore, a trend was seen towards a stronger association with postoperative recurrence. CONCLUSION: The current study could not confirm a different prognosis for CD patients with and without an inflamed appendix. In contrast, in patients with a previous appendectomy a trend was seen towards increased postoperative recurrence, which might be related to the higher incidence of penetrating disease.